Depersonalization disorder (DPD) is a chronic, potentially disabling and very understudied psychiatric disorder, generally believed to be rare and treatment-refractory. Patients with DPD suffer from a persistent or recurrent sense of unreality and detachment from various aspects of the self, which leads to great distress or interference with interpersonal or occupational functioning. Although there is a marked paucity of systematic research on the epidemiology, phenomenology and treatment of DPD, preliminary data suggest that serotonin reuptake inhibitors may be of significant therapeutic benefit. However, no randomized, controlled, double-blind pharmacological treatment studies have been conducted to date in DPD. Fluoxetine, a selective serotonin reuptake inhibitor, appears to have efficacy in the treatment of DPD in preliminary studies. Open treatment data from the literature and from our own pilot work suggest a 56% to 71% response rate. Our double-blind pilot treatment data with the serotonin reuptake inhibitor clomipramine appear similarly promising, with a 50% response rate for adequate clomipramine trials, but also suggest a marked intolerance for the side-effects of tricyclics. To systematically assess the efficacy of fluoxetine in the treatment of DPD, 80 patients will be entered into an outpatient double-blind randomized 12-week parallel fluoxetine versus placebo treatment study. Outcome will be rated weekly by the treating psychiatrist and every two weeks by an independent evaluator blind to dosage and side-effects. Responders will continue in a double-blind maintenance phase for an additional 6 months to assess durability of response. When completed, the study should provide systematic information on the efficacy of fluoxetine in the acute treatment of DPD, on the durability of response with six months of continued maintenance, on the change in psychiatric disability with successful treatment, and on the effect of comorbid Axis 1 and Axis Il diagnoses on treatment outcome.